WO2004108685A1 - Produits aryl-heteroaromatiques, compositions les contenant et utilisation - Google Patents

Produits aryl-heteroaromatiques, compositions les contenant et utilisation Download PDF

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Publication number
WO2004108685A1
WO2004108685A1 PCT/FR2004/001379 FR2004001379W WO2004108685A1 WO 2004108685 A1 WO2004108685 A1 WO 2004108685A1 FR 2004001379 W FR2004001379 W FR 2004001379W WO 2004108685 A1 WO2004108685 A1 WO 2004108685A1
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Prior art keywords
phenyl
piperazin
methanone
pyrrol
imidazol
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PCT/FR2004/001379
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English (en)
French (fr)
Inventor
Patrick Mailliet
Alain Le Brun
Fabienne Thompson
Gilles Tiraboschi
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Aventis Pharma S.A.
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Priority claimed from FR0306719A external-priority patent/FR2855825B1/fr
Application filed by Aventis Pharma S.A. filed Critical Aventis Pharma S.A.
Priority to BRPI0411001-3A priority Critical patent/BRPI0411001A/pt
Priority to JP2006508355A priority patent/JP4805813B2/ja
Priority to AU2004245269A priority patent/AU2004245269A1/en
Priority to CA002528093A priority patent/CA2528093A1/fr
Priority to MXPA05012929A priority patent/MXPA05012929A/es
Priority to EP04767247A priority patent/EP1641765A1/fr
Publication of WO2004108685A1 publication Critical patent/WO2004108685A1/fr
Priority to IL172222A priority patent/IL172222A0/en
Priority to HK06114181.4A priority patent/HK1093339A1/xx

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel chemical compounds, particularly novel aryl-heteroaromatic products, compositions containing them, and their use as medicaments. More particularly, the invention relates, in a first aspect, to new aryl-heteroaromatic products exhibiting anticancer activity, and in particular tubulin polymerization inhibitory activity.
  • the 1,2,5-oxadiazole is optionally in the form of an N-oxide.
  • R is phenyl. Identified Products [CAS Numbers]: [157066-46-1], [157066-44-9], [157066-43-8], [157066-42-7].
  • Patent Application WO 02/30927 discloses an isoxazole derivative on page 95; N- (4- ⁇ 4- [3- (2-chloro-phenyl) -5-methyl-isoxazole-4-carbonyl] -piperazin-1-yl ⁇ -phenyl) -N- [3- (cyano-benzyl) ) -3-H-imidazol-4-yl-methyl] -benzamide.
  • This product described as prenyl transferase protein inhibitor and its use are not part of the present invention.
  • WO 04/002965 published after the priority date of the present application, discloses piperazine derivatives useful for the treatment of cancer. All the products described in this patent application (17) are excluded from the present invention. Products with CAS number: 522598-56-7, 505088- 40-4,
  • A is N or C; 2) LGR 11 eesstt cchhooiissii pplormmii and
  • X and Y are independently selected from CR3, N, NR3, O or S; 4) E is CR4, N, NR4 or S;
  • R1, R2 are independently selected from the group consisting of aryl, heteroaryl, substituted aryl, substituted heteroaryl;
  • R3, R4 are independently selected from the group consisting of H, alyl, substituted alkyl, cycloalkyl, cycloalkylene, heterocyclyl, O-R7, S-R7, SO-R7, SO 2 - (R7), N (R7) (R8), halogen, aryl, heteroaryl, substituted cycloalkyl, substituted aryl, substituted heteroaryl;
  • R5, R6 are independently selected from the group consisting of H, (C1-C3) alkyl
  • R7, R8 are independently selected from the group consisting of H, (C1-C3) alkyl, (C1-C3) substituted alkyl; in racemic form, enriched in an enantiomer, enriched in a diastereoisomer, its tautomers, its prodrugs and its pharmaceutically acceptable salts, provided that the product of formula (I) is not one of the following compounds:
  • A is N or C
  • LG-R1 is selected from are preferred.
  • a preferred substituent R 1 may be selected from phenyl, phenyl substituted with at least one radical selected from halogen, CF 3, CN, NO 2, (C 1 -C 3) -alkyl, O-R 10, S-R 10, N (R 10) (R 11) ,
  • R10, R11 are independently selected from H, (C1-C3) -alkyl, (C1-C3) -alkyl halogen, (C1-C3) -alkyl-OH, (C1-C3) -alkyl-NH2, (C1-C3) -alkyl-COOH, (C1-C3) -alkyl-OCH3, (C1-C3) -alkyl-NHCH3, pyridyl, pyridyl substituted with at least one radical selected from halogen, (C1-C3) alkyl, O-R12, S-R12, N (R12) (
  • R 1 will be 3-substituted phenyl by halogen or (C 1 -C 3) -alkyl, (C 1 -C 3) -alkoxy, (C 1 -C 3) alkylamino, CONH 2, CO-NH- (CH 2) 2 -OH or NH-CO-CH3; or 3-pyridyl .; 2- or 3-pyridyl substituted with halogen, (C1-C3) -alkyl or (C1 -C3) -alkoxy.
  • R 1 is substituted phenyl
  • preferred combinations of substitution may be selected from 2,3-disubstituted phenyl, 2,5-disubstituted phenyl, 3-substituted phenyl, 3,5-disubstituted phenyl, 3,4-phenyl disubstituted, more preferentially among 3-substituted-phenyl, 3,5-disubstituted phenyl, 3,4-disubstituted phenyl.
  • R 1 is 2-pyridyl
  • preferred substitutions are selected from 2-pyridyl-4- or 6-substituted or 2-pyridyl-4,6-disubstituted.
  • R 1 is 3-pyridyl
  • preferred substitutions are 3-pyridyl-2- or
  • R 1 is phenyl substituted in the 3-position with a chloro radical or at the 3-position and 5-position with two methoxy radicals.
  • R 1 is phenyl substituted at the 3-position with a cyano radical, a carboxamide radical, a methoxy radical, or a hydroxymethyl radical.
  • a preferred substituent R2 may be selected from phenyl, phenyl substituted with at least one radical selected from halogen, alkyl, O-R10, S-R10, N (R10) (R11), wherein R10, R11 are independently selected from H, alkyl, halogenated alkyl; or 3-pyridyl.
  • a preferred substituent R 1 is selected from 3-methoxyphenyl, 3,5-dimethoxyphenyl, and 3-carboxamidophenyl.
  • a more preferred substituent R 1 is 3-carboxamidophenyl. Indeed, this substituent allows a significant improvement in the pharmacological properties of the products according to the invention.
  • Products according to the first aspect of the invention wherein X is C, and Y is CR3 are particularly preferred. These features make it possible to highlight significantly improved pharmacological properties compared with other derivatives, such as better activity in vivo or in vitro, a better pharmacokinetic profile, a better pharmacodynamic profile, an increased ease of preparation, or better bioavailability such as orally, or iv
  • the invention relates to pharmaceutical compositions comprising a product according to its first aspect, in combination with a pharmaceutically acceptable excipient.
  • a product according to the invention can be advantageously used as a tubulin polymerization inhibiting agent, as an agent inhibiting the proliferation of tumor cells, to promote the disintegration of cell clusters originating from a vascular tissue, or for the manufacture of a drug useful for treating a pathological condition, preferably cancer.
  • products of general formula (Ia) or (Ib) according to the invention in which L is C (O) may be prepared by coupling of an ortho-substituted heteroarylcarboxylic acid of the carboxylic function with an aryl radical.
  • heteroaryl, of general formula (II) in which A, X, Y, E and R2 are defined as above, with, respectively, a piperazine derivative of general formula (IIIa) or a derivative of 1,2,3 , 6-tetrahydropyridine of the general formula (IIIb), in which R1 is defined as previously according to scheme 1:
  • X, Y, E and R2 are defined as above, are commercial or can be obtained according to the general methods of synthesis known to those skilled in the art.
  • R6 are defined as above, are either commercial or prepared according to conventional methods known to those skilled in the art.
  • N1-aryl (heteroaryl) ation according to scheme 2, of piperazines bearing a protective group on nitrogen 4, is particularly advantageous in the context of the invention:
  • aryl (heteroaryl) reaction of piperazines can be carried out under the conditions described in Biorg. Med. Chem. Leti, 11, 1375 (2001) or in Biorg. Med. Chem., 10, 3817 (2002).
  • Another method for synthesizing aryl (heteroaryl) piperazines, particularly advantageous in the context of the invention, when R 5 and R 6 represent hydrogen atoms, consists in reacting an aryl (heteroaryl) amine with a bis ( 2-hydroxy- or 2-haloethyl) amine, at a temperature above 100-120 ° C according to scheme 3: OH (Hal)
  • the 1,2,3,6-tetrahydropyridine derivatives (IIIb), in which R 1, R 5 and R 6 are defined as above, are either commercial or prepared according to conventional methods known to those skilled in the art.
  • the action, according to scheme 4, of an organometallic derivative of aryl (heteroaryl), such as an organomagnesium, an organolithium or an organoceriac, on a piperidin-4-one derivative whose atom nitrogen is substituted with a protecting group is particularly advantageous.
  • products of general formula (Ia) or (Ib) according to the invention in which L is C (S) may be prepared by thionation of a compound of general formula respectively (Ia) or (Ib), wherein L is C (O), by any of the thionation methods known to those skilled in the art, operating according to Scheme 6:
  • products of general formula (Ia) or (Ib) according to the invention in which L is C (NH) may be prepared from nitriles derived from the products of general formula (II), using the various methods known to those skilled in the art, according to the reaction sequences of Scheme 7:
  • products of general formula (Ia) according to the invention in which L is C (NR7), with R7 equal to or different from the hydrogen atom can be prepared from products of general formula ( la) in which L is C (O) and / or C (S), using the various methods known to those skilled in the art, according to the reaction sequences of scheme 8:
  • X is an oxygen atom
  • products in accordance with the invention can also be prepared on a solid phase, according to reaction scheme 9:
  • LC / MS Purification The products were purified by LC / MS using a Waters FractionsLynx system consisting of a Waters Model 600 gradient pump, a Waters Model 515 regeneration pump, a Waters Reagent dilution pump Manager, Waters model 2700 auto-injector, two Rheodyne Model LabPro valves, a Model 996 Waters diode array detector, a Waters model ZMD mass spectrometer and a Gilson model 204 fraction collector The system was controlled by the Waters FractionLynx software.
  • the separation was carried out alternately on two Waters Symmetry columns (C- ⁇ 8 , 5 ⁇ M, 19 ⁇ 50 mm, catalog number 186000210), a column being regenerated by a 95/5 (v / v) water / acetonitrile mixture containing 0 , 07% (v / v) of acid trifluoroacetic, while the other column was being separated. Elution of the columns was performed using a linear gradient of 5-95% acetonitrile containing 0.07% (v / v) trifluoroacetic acid in water containing 0.07% (v / v) d. trifluoroacetic acid at a flow rate of 10 ml / min.
  • one thousandth of the effluent is separated by an LC Packing Accurate, diluted with methyl alcohol at a flow rate of 0.5 mL / min and sent to the detectors, at a rate of 75%. to the diode array detector, and the remaining 25% to the mass spectrometer.
  • the remainder of the effluent (999/1000) is sent to the fraction collector where the flow is eliminated until the mass of the expected product is detected by the FractionLynx software.
  • the molecular formulas of the expected products are provided to the FractionLynx software which triggers the product collection when the detected mass signal corresponds to the [M + H] + and / or [M + Na] + ion.
  • the LC / MS analyzes were performed on a Micromass LCT model connected to an HP 1100.
  • the abundance of the products was measured using an HP G1315A diode array detector over a range of 200-600 nm and a Sedex 65 light scattering detector.
  • Mass spectra mass spectra were acquired over a range of 180 to 800. The data were analyzed using the Micromass MassLynx software.
  • the separation was carried out on a Hypersil BDS C18 column, 3 ⁇ m (50 ⁇ 4.6 mm), eluting with a linear gradient of 5 to 90% of acetonitrile containing 0.05% (v / v) of trifluoroacetic acid ( TFA) in water containing 0.05% (v / v) TFA in 3.5 min at a flow rate of 1 mL / min.
  • the total analysis time, including the rebalancing period of the column, is 7 minutes.
  • Example 1 [4- (3-Chloro-phenyl) -piperazin-1-yl] - (1-phenyl-1H-imidazol-5-yl) -methanone Step 1: In a 100 ml three-necked flask, 3.5 g of ethyl 1-phenyl-1-H-imidazol-5-yl-carboxylate, which can be prepared according to Tetrahedron Lett, are dissolved. (2000) 41, 5453-56, in 50 mL of ethanol, then 25 mL of water and 16.2 mL of an 85% aqueous potassium hydroxide solution are added, followed by stirring for 20 hours at room temperature.
  • reaction medium is taken up in 100 ml of water and then washed 3 times with 75 ml of diethyl ether.
  • the aqueous phase is concentrated in vacuo and the residue is taken up in 10 ml of methanol and then filtered.
  • the filtrate is finally taken up in 25 ml of isopropyl ether, drained and washed twice with 2 ml of isopropyl ether.
  • 1-phenyl-1-H-imidazol-5-yl-carboxylic acid in the form of a brown solid, used as such in the next step.
  • Step 2 In a 100 mL tricolor under an argon atmosphere, to a solution of 0.5 g of 1-phenyl-1-H-imidazole-5-yl-carboxylic acid in 25 mL of dichloromethane, are added successively 342 ⁇ l of oxalyl chloride and a few drops of dimethylformamide are stirred for 2 hours at room temperature. The solution thus obtained is transferred into a dropping funnel, and is added, dropwise, to a solution, cooled to 0 ° C. under an argon atmosphere, of 575 mg of 1- (3-chlorophenyl) piperazine in 25 ml.
  • Step 1 By operating as in step 2 of Example 1, but starting from 350 mg of ethyl 4-phenyl-1-H-imidazol-5-yl-carboxylate - which can be prepared according to Tetrahedron Lett. . (1994), 35, 1635-38 and 1.6 ml of an 85% aqueous potassium hydroxide solution in 5 ml of ethanol and 2.5 ml of water give 218 mg of 4- phenyl-1-H-imidazol-5-yl-carboxylic acid, in the form of a beige solid used as it is in the next step.
  • Step 2 By operating as in step 2 of Example 1, but starting from a portion of 188 mg of 4-phenyl-1-H-imidazol-5-yl-carboxylic acid and 128 ⁇ l of oxalyl chloride in 10 ml of dichloromethane, and on the other hand 216 mg of 1- (3-chlorophenyl) piperazine in 10 ml of dichloromethane containing 210 ⁇ l of triethylamine and 5 ⁇ l of 4-dimethylaminopyridine, for 20 hours at room temperature.
  • Step 2 The procedure is as in Step 2 of Example 1, but in a stem tube of 10 mL under argon and from 80 mg of 3-phenyl-1H-pyrrol-2-yl-carboxylic acid. and 112 ⁇ l of oxalyl chloride in 5 ml of dichloromethane.
  • the reaction medium is concentrated under reduced pressure, and the acid chloride thus obtained is dissolved in 5 ml of tetrahydrofuran, and then 76.3 mg of 3-chloro-phenyl) piperazine and 81.8 ⁇ l of triethylamine and then stirred for 20 hours at room temperature.
  • the crude product is purified by LCMS according to the procedure described above.
  • Example 5 The procedure is as in Example 5, but starting with 1 g of 4-phenyl-1-H-imidazol-5-yl-carboxylic acid, obtained in step 1 of Example 3, and 1.2 g of 1- (3,5-dimethoxy-phenyl) piperazine in 90 ml of dichloromethane in the presence of 1.1 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 0.79 g of 1-hydroxybenzotriazole hydrate (HOBT), with stirring at room temperature for 48 hours.
  • EDCI 1-(2-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Example 5 The procedure is as in Example 5, but starting from 580 mg of 1-phenyl-1-H-imidazol-5-yl-carboxylic acid, obtained in step 1 of Example 1, and 685 mg of 1- (3,5-dimethoxy-phenyl) piperazine in 50 ml of dichloromethane, in the presence of 650 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 460 mg of 1-hydroxybenzotriazole hydrate (HOBT), with stirring at room temperature for 48 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Example 5 The procedure is as in Example 5, but starting from 376 mg of 1-phenyl-1-H-imidazol-5-yl-carboxylic acid, obtained in step 1 of example 1, and 520 mg of 1- (3-cyano-phenyl) piperazine, which can be prepared according to Tetrahedron Lett. (2000), 56 (24), 4107-10, in 34 mL of dichloromethane, in the presence of 422 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 297 mg of 1-hydrate. hydroxybenzotriazole (HOBT), with stirring at room temperature for 20 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT hydroxybenzotriazole
  • Example 5 The procedure is as in Example 5, but starting with 200 mg of 4-phenyl-1-H-imidazol-5-yl-carboxylic acid, obtained in step 1 of Example 3, and 276 mg of 1- (3-cyano-phenyl) piperazine, which can be prepared according to Tetrahedron Lett. (2000), 56 (24), 4107-10, in 34 mL of dichloromethane, in the presence of 224 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 158 mg of 1-hydrate. hydroxybenzotriazole (HOBT), with stirring at room temperature for 20 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT hydroxybenzotriazole
  • Example 5 The procedure is as in Example 5, but starting from 562 mg of 4-phenyl-1-H-pyrrole-3-yl-carboxylic acid, which can be prepared according to Med. Chem. Res. (1997), 7 (2), 98-108, and 590 mg of 1- (3-chlorophenyl) piperazine in 90 ml of dichloromethane, in the presence of 632 mg of 1- (3-dimethylaminopropyl) hydrochloride. 3-ethylcarbodiimide (EDCI) and 446 mg of 1-hydroxybenzotriazole hydrate (HOBT), with stirring at room temperature for 72 hours.
  • EDCI 3-ethylcarbodiimide
  • HOBT 1-hydroxybenzotriazole hydrate
  • Example 5 The procedure is as in Example 5, but starting from 201 mg of 1-methyl-4-phenyl-1-H-pyrrole-3-yl-carboxylic acid, which can be prepared according to Med. Chem. Res. (1997), 7 (2), 98-108, and 222 mg of 1- (3,5-dimethoxyphenyl) piperazine in 20 ml of dichloromethane, in the presence of 211 mg of 1- (3-dimethylaminopropyl) hydrochloride. ) -3-ethylcarbodiimide (EDCI) and 148 mg of 1-hydroxybenzotriazole hydrate (HOBT), with stirring at room temperature for 72 hours.
  • EDCI 1-methyl-4-phenyl-1-H-pyrrole-3-yl-carboxylic acid
  • Example 5 The procedure is as in Example 5, but starting from 200 mg of 2-mercapto-5-phenyl-1-H-imidazol-4-yl-carboxylic acid, which can be prepared according to Chem. Pharm. Bull. (1984), 32 (7), 2536-43, and 178.6 mg of 1- (3-chlorophenyl) piperazine in 15 mL of dichloromethane, in the presence of 192 mg of 1- (3-dimethylaminopropyl) hydrochloride. ) -3-ethylcarbodiimide (EDCI) and 135 mg of 1-hydroxybenzotriazole hydrate (HOBT), with stirring at room temperature for 24 hours. After concentration under reduced pressure, 20 ml of water are added.
  • 2-mercapto-5-phenyl-1-H-imidazol-4-yl-carboxylic acid which can be prepared according to Chem. Pharm. Bull. (1984), 32 (7), 2536-43, and 178.6 mg of 1- (3-chlor
  • Step 1 In a 250 mL tricolor, 1.2 g of ethyl 2-phenyl-1-H-pyrrol-3-yl-carboxylate, which can be prepared according to J. Chem. Soc. Perkin Trans I 1994 (17), 2355-56, in 80 mL of ethanol and 19.5 mL of 1N aqueous sodium hydroxide solution; then reflux for 48 hours. After concentrating the ethanol under reduced pressure, the reaction medium is dissolved in 25 ml of distilled water. The aqueous solution obtained is washed with 3 times 10 ml of ethyl acetate and then acidified by addition of 39.5 ml of a 1 N aqueous solution of hydrochloric acid.
  • Step 2 The procedure is as in Example 5, but starting from 375 mg of 2-phenyl-1-H-pyrrol-3-yl-carboxylic acid, prepared above, and 440 mg of 1- ( 3,5-dimethoxy-phenyl) piperazine in 30 mL of dichloromethane, in the presence of 420 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 27 mg of 1-hydroxybenzotriazole hydrate (HOBT) stirring at room temperature for 72 hours, after 24 hours, 20 ml of dichloromethane were added.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Example 5 The procedure is as in Example 5, but starting from 189 mg of 4-phenyl-1-H-imidazol-5-yl-carboxylic acid, obtained in step 1 of Example 3, and 278 mg of 1- (3-carboxamido-phenyl) piperazine dihydrochloride, which can be prepared according to WO98 / 00400, in 35 ml of dichloromethane, in the presence of 422 ⁇ l of triethylamine, 211 mg of 1-chlorohydrate ( 3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) and 148 mg of 1-hydroxybenzotriazole hydrate (HOBT), with stirring at room temperature for 20 hours. The precipitate obtained is drained, washed successively with
  • Example 5 The procedure is as in Example 5, but starting from 195 mg of 2-phenyl-1H-pyrrol-3-yl-carboxylic acid, obtained in step 1 of Example 21, and 280 mg of 1- (3-carboxamido-phenyl) piperazine dihydrochloride, which may be prepared according to WO9800400, in 35 ml of dichloromethane, in the presence of 420 ⁇ l of triethylamine, 210 mg of 1- (3-dimethylaminopropyl) -3-hydrochloride ethylcarbodiimide (EDCI) and 150 mg of 1-hydroxybenzotriazole hydrate (HOBT), with stirring at room temperature for 20 hours.
  • 1- (3-carboxamido-phenyl) piperazine dihydrochloride which may be prepared according to WO9800400, in 35 ml of dichloromethane, in the presence of 420 ⁇ l of triethylamine, 210 mg of 1- (3-dimethylaminopropy
  • the precipitate obtained is drained, washed successively with 2 times 5 ml of dichloromethane, 2 times 20 ml of water, 2 times 20 ml of a saturated aqueous solution of sodium hydrogencarbonate and then twice with 20 ml of water.
  • the precipitate is then purified by flash chromatography on silica gel (60, 30-75 ⁇ M) eluting with a mixture of dichloromethane and ethanol (90-10 by volume).
  • Example 5 The procedure is as in Example 5, but starting from 189 mg of 2-phenyl-1H-pyrrol-3-yl-carboxylic acid, obtained in step 1 of Example 21, and of 200 mg of 1- (3-chloro-phenyl) piperazine in 15 mL of dichloromethane, in the presence of 210 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 13 mg of 1-hydroxybenzotriazole hydrate (HOBT), with stirring at room temperature for 72 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • the precipitate obtained is drained, washed successively with 2 times 5 ml of dichloromethane, 2 times 20 ml of water, 2 times 20 ml of a saturated aqueous solution of sodium hydrogencarbonate and then twice with 20 ml of water.
  • the precipitate is then purified by flash chromatography on silica gel (60; 30-75 ⁇ M) eluting with a mixture of dichloromethane and ethanol (95-5 by volume).
  • Example 5 The procedure is as in Example 5, but starting from 188 mg of 4-phenyl-1-H-imidazol-5-yl-carboxylic acid, obtained in step 1 of Example 3, and 192 mg of 1- (3-methoxy-phenyl) piperazine in 20 ml of dichloromethane, in the presence of 211 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 148 mg of hydrate of 1-hydroxybenzotriazole (HOBT), stirring at room temperature for 20 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole
  • Step 1 Tert-butyl 4- (3-Difluoromethoxy-phenyl) -piperazin-1-yl-carboxylate
  • the reaction mixture is diluted with water (20 ml) and then extracted with ethyl acetate (2 ⁇ 30 ml). The organic extracts are combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure.
  • the compound obtained is purified by chromatography on silica gel (AIT cartridge, Ref FC-25 Si-BP-SUP, 20-40 ⁇ m, dichloromethane eluent, flow rate of 20 ml / min). The fractions containing the expected compound are combined and then evaporated under reduced pressure.
  • the expected tert-butyl 4- (3-difluoromethoxy-phenyl) -piperazin-1-yl-carboxylate (253 mg), which has the following characteristics, is isolated.
  • Step 2 1- (3-Difluoromethoxy-phenyl) -piperazine Hydrochloride
  • a solution of tert-butyl 4- (3-difluoromethoxyphenyl) -piperazin-1-carboxylate (253 mg, 3.8 mmol) in a mixture of dioxane (1016 ⁇ l) and hydrochloric acid (963 ⁇ l).
  • the mixture reactionnei is stirred at 20 ° C for 48 hours.
  • the solid formed is filtered off, washed (diisopropyl ether, 10 ml) and dried under reduced pressure.
  • Step 3 The procedure is as in Example 5, but starting from 376 mg of 4-phenyl-1-H-imidazol-5-yl-carboxylic acid, obtained in step 1 of Example 3, and of 602 mg of 1- (3-difluoromethoxy-phenyl) -piperazine dihydrochloride in 50 ml of dichloromethane, in the presence of 0.618 ml of triethylamine, 422 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( EDCI) and 296 mg of 1-hydroxybenzotriazole hydrate (HOBT), with stirring at room temperature for 20 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • MCPBA meta-chloro-perbenzoic acid
  • Example 32 The procedure is as in Example 32, but the first fraction is collected. After acidification of this elution fraction with 132 ⁇ l of 1 M hydrochloric acid, 53 mg of 3- ⁇ 3- [4- (3-chlorophenyl) -piperazin-1-carbonyl] hydrochloride are collected. methyl phenyl-pyrrol-1-yl ⁇ propionate; as amorphous beige solid whose characteristics are as follows:
  • Step 1 391.5 mg of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - (4-phenyl-1-H-pyrrol-3-yl) -methanone, prepared by stirring.
  • Example 16 in 10 mL of pyridine. After cooling to 0 ° C., 90 mg of 60% sodium hydride in oil, previously washed by decantation in toluene, are added portionwise and the mixture is stirred at 0 ° C. for 30 minutes. 241 mg of (2-bromoethoxy) -tert-butyl dimethylsilane are then added and the mixture is heated at 60 ° C. for 3 hours and then stirred at room temperature for 20 hours.
  • the pyridine is concentrated under reduced pressure and the residue is taken up in 50 ml of water and then extracted with 3 times 25 ml of ethyl acetate. After drying over magnesium sulphate and concentration under reduced pressure, purification is obtained by flash chromatography on silica gel (60, 30-75 ⁇ M), eluting with a mixture of dichloromethane and methanol (97.5-2.5 g).
  • Step 1 In a 250 ml three-necked flask, a solution of 3.25 g of 1-boc-piperazine in 115 ml of toluene is placed, then 369.4 mg of (R) - (+) - 2,2 bis (diphenylphosphino) -1,1'-binaphthyl, 3.176 g of 3-bromobenzonitrile, 133.2 ml of palladium acetate and 2.516 g of sodium tert-butoxide. The reaction mixture is stirred and heated at 80 ° C for 16 hours and then diluted with 110 mL of water. The aqueous phase is decanted and then extracted with 120 mL of ethyl acetate.
  • the organic extracts are combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure.
  • the compound obtained is purified by chromatography on silica gel (AIT cartridge, Ref FC-150-Si-BP-SUP, 20-40 ⁇ m, deposition solvent: dichloromethane, then cyclohexane elution / ethyl acetate 75/25 v v / v, flow rate of 20 mL / min until crystallization of the compound on the column).
  • the silica column is flowed in 8 equal sections, the silica of each section being then extracted with ethyl acetate (20 ml) yielding different fractions.
  • Step 2 In a 250 ml flask, place a solution of 3.81 g of tertobutyl 4- (3-cyano-phenyl) -piperazin-1-yl-carboxylate, obtained previously in 100 ml of methanol; then 24 ml of a molar solution of aqueous sodium hydroxide is added. The reaction mixture is refluxed for 36 hours and then evaporated under reduced pressure. The residue is taken up in 150 mL of ethyl acetate and 150 mL of water and decanted. The aqueous phase is extracted with 100 ml of ethyl acetate.
  • Step 3 In a 100 mL flask, a solution of 2.01 g of tert-butyl 4- (3-carbamoyl-phenyl) -piperazin-1-yl-carboxylate in 8 mL of dioxane is placed; then 8 ml of a solution of 4M hydrochloric acid in dioxane is added and stirred at 20 ° C for 16 hours. The solid formed is filtered, washed with ethyl ether and dried under reduced pressure. In this way 1. 57 g of 3- (piperazin-1-yl) -benzamide are obtained, the characteristic of which is as follows:
  • Step 4 In a 100 ml three-necked flask placed under argon, a mixture of 500 mg of 3-phenyl-1H-pyrrol-2-yl-carboxylic acid, obtained in step 1 of example 6, is placed. 563.2 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 397 mg of 1-hydroxybenzotriazole (HOBT) and 710.2 mg of 3- (piperazin-1-yl) benzamide under stirring in 40 mL of dichloromethane; then 1, 24 ml of triethylamine is added.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole
  • 3- (piperazin-1-yl) benzamide under stirring in 40 mL of dichloromethane; then 1, 24 ml of triethylamine is added.
  • the reaction mixture is stirred at 20 ° C for 16 hours and then diluted with 50 mL of dichloromethane and 50 mL of water. After decantation, the mixture is extracted with 20 ml of dichloromethane. The organic extracts are combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure.
  • the crude compound obtained is taken up in ethyl acetate (15 ml) and methanol (5 ml), dissolved and left at 20 ° C. for 48 hours. The solid formed is filtered, washed with ethyl acetate (5 mL) and then with ethyl ether and dried under reduced pressure.
  • the reaction mixture is diluted with water (15 mL) and extracted with ethyl acetate (15 mL).
  • the aqueous phase is extracted with ethyl acetate (2 ⁇ 10 mL).
  • the organic extracts are combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure.
  • the compound obtained is purified by chromatography on silica gel (Cartridge 26 x 135, Ref 1511-1000, silica 10g, 15-40 ⁇ m, eluent cyclohexane / ethyl acetate, 9/1 v / v, flow rate of 10 mL / min).
  • Step 2 To a solution of 200 mg of 2-amino-4-phenylthiazol-5-ylcarboxylic acid, and 202 mg of 1- ( 3,5-dimethoxy-phenyl) -piperazine in 25 ml of dichloromethane are added 192 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 135 mg of 1-hydroxybenzotriazole hydrate (HOBT). .
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Step 1 To a solution of 3.5 g of ethyl 2-methyl-5-phenyl-1H-imidazol-4-yl-carboxylate, which can be obtained according to the patent application WO95 / 04724, in 30 mL distilled water and 60 ml of ethanol is added 1 g of potassium hydroxide pellets. After heating for 20 hours under reflux and then returning to ambient temperature, the reaction mixture is concentrated under reduced pressure, and the residue is acidified with 1N hydrochloric acid. Thus, after filtration of the solid formed, 3 g of 2-methyl-5-phenyl-1H-imidazol-4-yl-carboxylic acid, in the form of a beige solid, the characteristic of which is as follows:
  • Step 2 To a solution of 140 mg of 2-methyl-5-phenyl-1H-imidazol-4-yl-carboxylic acid, in 15 mL of dichloromethane, 146 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI),
  • the pyridine is concentrated under reduced pressure and the residue is taken up in 50 ml of water and then extracted with 3 times 25 ml of ethyl acetate.
  • the combined "dichloromethane" phases are concentrated to dryness under reduced pressure and the residue is purified by flash chromatography on silica gel (60, 30-75 microM) eluting with a mixture of dichloromethane and methanol (95-5 by volume) .
  • Methyl 2- ⁇ 3- [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] carbonyl-2-phenyl-1H-pyrrol-1-yl ⁇ -acetate 350 mg. - (3,5-dimethoxy-phenyl) -piperazin-1-yl] - (2-phenyl-1H-pyrrol-3-yl) -methanone, prepared in Example 8, in 15 mL of pyridine. After cooling to 0 ° C., 54 mg of 60% sodium hydride in oil, previously washed by decantation in toluene, are added portionwise, and the mixture is stirred at 0 ° C. for 30 minutes.
  • Example 5 The procedure is as in Example 5, but on the one hand 430 mg of 1-methyl-2-phenyl-1-H-pyrrol-3-yl-carboxylic acid, which can be prepared as in step 1 of Example 21, and on the other hand 420 mg of 1- (3-carboxamido-phenyl) -piperazine dihydrochloride, which can be prepared according to WO98 / 00400, in 50 ml of dichloromethane, in the presence of 320 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 20 mg of 1-hydroxybenzotriazole hydrate (HOBT) and 0.6 mL of triethylamine, with stirring at room temperature for 20 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Step 1 391.5 mg of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - (2-phenyl-1-H-pyrrol-3-yl) -methanone, prepared by stirring.
  • Example 8 in 20 mL of pyridine. After cooling to 0 ° C., 64.5 mg of 60% sodium hydride in oil, previously washed by decantation in toluene, are added portionwise, and the mixture is stirred at 0 ° C. for 30 minutes. 0.25 ml of (2-bromoethoxy) -tert-butyl dimethylsilane are then added and the mixture is stirred at room temperature for 20 hours.
  • Step 2 To a solution of 550 mg of ⁇ 1- [2- (tert-butyl-dimethyl-silanyloxy) -ethyl] -2-phenyl-1H-pyrrol-3-yl ⁇ - [4- (3.5 g) (dimethoxy-phenyl) -piperazin-1-yl] -methanone in 20 ml of tetrahydrofuran are added 8 ml of a 1 M solution of tetra-N-butylammonium fluoride in tetrahydrofuran.
  • Step 2 The procedure is as in Example 5, but on the one hand 120 mg of 2-trifluoromethyl-4-phenyl-1-H-imidazol-5-yl-carboxylic acid, and secondly 130 mg of 1- (3-carboxamido-phenyl) -piperazine dihydrochloride, which may be prepared according to WO98 / 00400, in 20 ml of dichloromethane, in the presence of 99 mg of 1- (3-dimethylaminopropyl) -3-hydrochloride ethylcarbodiimide (EDCI), 70 mg of 1-hydroxybenzotriazole hydrate (HOBT) and 0.20 ml of triethylamine, with stirring at room temperature for 20 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-hydrochloride ethylcarbodiimide
  • HOBT 1-hydroxybenzotriazole hydrate
  • Example 55 The procedure is as in Example 55, but starting from 200 mg of 3- [4- (2-mercapto-4-phenyl-1H-imidazol-5-ylcarbonyl) -piperazin-1-yl] -benzonitrile obtained in Example 52, 33 mg of sodium methylate and 35 ⁇ l of methyl iodide in 20 ml of methanol. After recrystallization from diisopropyl ether, 106 mg of 3- [4- (2-methylsulfanyl-4-phenyl-1H-imidazol-5-ylcarbonyl) -piperazin-1-yl] benzonitrile, in the form of a white powder, the characteristic of which is as follows:
  • Step 1 850 mg of 4-Fertbutylcarbonyloxy-1- (3-hydroxymethyl-phenyl) piperazine, which can be prepared according to WO00 / 15646, are dissolved in 40 ml of dioxane. 3.64 ml of a 4N solution of hydrochloric acid in dioxane are then added and the mixture is stirred for 1 hour at 0 ° C. The precipitate formed is drained, washed with diethyl ether and dried under reduced pressure. 770 mg of 1- (3-hydroxymethyl-phenyl) -piperazine dihydrochloride are thus obtained in the form of a yellow powder which is used as it is in the next step.
  • Step 2 The procedure is as in Example 5, but starting from 145 mg of 2-hydroxy-4-phenyl-1-H-imidazol-5-yl-carboxylic acid, which can be prepared according to Heterocycles 1984, 22 (8), 1763-6998-108, and on the other hand
  • Example 5 The procedure is as in Example 5, but starting from 1.404 g of 4-phenyl-1-H-pyrrol-3-yl-carboxylic acid, which can be prepared according to Med. Chem. Res. 1997, 7 (2), 98-108, and secondly 2.086 g of 1- (3-carboxamido-phenyl) -piperazine dihydrochloride, which can be prepared according to WO98 / 00400, in 100 ml of dichloromethane, in 1.
  • Example 5 The procedure is as in Example 5, but starting with 200 mg of 2-trifluoromethyl-4-phenyl-1-H-imidazol-5-yl-carboxylic acid, prepared as in Step 1 of Example 54, and 174 mg of (3,5-dimethoxy-phenyl) -piperazine, in 30 ml of dichloromethane, in the presence of 165 mg of 1- (3-dimethylaminopropyl) hydrochloride. ethylcarbodiimide (EDCI) and 116 mg of 1-hydroxybenzotriazole hydrate (HOBT), with stirring at room temperature for 72 hours.
  • EDCI ethylcarbodiimide
  • HOBT 1-hydroxybenzotriazole hydrate
  • Step 2 To a solution of 400 mg of 3- ⁇ 4- [1- (tert-butyl-dimethyl-silanyloxy) -ethyl-4-phenyl-1H-pyrrol-3-yl-carbonyl] -piperazine-1 4-Benzamide in 12 ml of tetrahydrofuran are added 6 ml of a 1 M solution of tetra-N-butylammonium fluoride in tetrahydrofuran. After stirring for 20 hours at 20 ° C., 50 ml of ethyl acetate are added, the mixture is washed with 3 times 25 ml of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure.
  • Step 1 13 g of ethyl 2-mercapto-4-phenyl-1H-imidazol-5-yl-carboxylate, which can be prepared according to Chem. Pharm. Bull. 1984, 32 (7), 2536-43, are dissolved in 500 mL of methanol. After cooling to 0 ° C., 3.4 g of sodium methylate are added portionwise and the mixture is stirred for 30 minutes while allowing to return to ambient temperature. It is cooled again to 0 ° C., a solution of 3.3 g of methyl iodide in 25 ml of methanol is added dropwise and the mixture is refluxed for 8 hours.
  • Step 2 7 g of ethyl 2-methylsulfanyl-4-phenyl-1H-imidazol-5-yl-carboxylate are dissolved in 200 mL of methanol, then 24.6 g of oxone® - or potassium peroxomono sulfate (2KHSO 5. KHSO4, K 2 SO 4 ) - in solution in 100 mL of water. After stirring for 20 hours at room temperature, 200 ml of water are added and then the mixture is extracted three times with 100 mL of ethyl acetate. The combined organic phases are washed with water, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure.
  • Step 4 The procedure is as in Example 5, but starting from 444 mg of 2-methylsulfonyl-4-phenyl-1H-imidazol-5-yl-carboxylic acid on the one hand and of 333 mg of (3,5-dimethoxy-phenyl) -piperazine in 37.5 mL of dichloromethane in the presence of 316 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 223 mg of hydrate
  • Example 5 The procedure is as in Example 5, but starting on the one hand with 133 mg of 1-methyl-4-phenyl-1-H-pyrrol-3-yl-carboxylic acid, which can be prepared according to Med. Chem. Res. (1997), 7 (2), 98-108, and 175 mg of 1- (3-hydroxymethyl-phenyl) piperazine dihydrochloride, prepared as in step 1 of Example 57, in 25 ml of dichloromethane, in the presence of 139 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 98 mg of 1-hydroxybenzotriazole hydrate (HOBT) and 204 ⁇ l of triethylamine, with stirring at room temperature for 20 minutes.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Example 5 The procedure is as in Example 5, but starting with 600 mg of 2-methylsulfonyl-4-phenyl-1H-imidazol-5-yl-carboxylic acid, prepared in step 3 of Example 67, and 528 mg of 1- (3-cyanophenyl) piperazine dihydrochloride, prepared according to Tetrahedron Lett. 2000, 56 (24), 4107-10, in 50 mL of dichloromethane, in the presence of 428 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 301 mg of 1-hydroxybenzotriazole hydrate. (HOBT) and 627 ⁇ L of triethylamine, with stirring at room temperature for 20 hours.
  • 1- (3-cyanophenyl) piperazine dihydrochloride prepared according to Tetrahedron Lett. 2000, 56 (24), 4107-10, in 50 mL of dichloromethane, in the presence of 428 mg of 1- (3-
  • Example 5 The procedure is as in Example 5, but starting with 600 mg of 2-methylsulfonyl-4-phenyl-1H-imidazol-5-yl-carboxylic acid, prepared in step 3 of Example 67, and 564 mg of 1- (3-carboxamidophenyl) piperazine dihydrochloride in 68 mL of dichloromethane, in the presence of 428 mg. of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 301 mg of 1-hydroxybenzotriazole hydrate (HOBT) and 627 ⁇ l of triethylamine, with stirring at room temperature for 20 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Step 1 A solution of 2.6 g of tert-butyl 4- (3-cyano-phenyl) -piperazin-1-yl-carboxylate (obtained as described in step 1 of Example 39) in dioxane (15 ml) a solution of 4M hydrochloric acid in dioxane (11.6 ml) is added and the reaction mixture is stirred at 20 ° C.
  • Step 2 In a 100 ml three-necked flask placed under argon, a mixture of 300 mg of 3-phenyl-1H-pyrrol-2-yl-carboxylic acid, obtained in step 1 of example 6, is placed. 307 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 216 mg of 1-hydroxybenzotriazole (HOBT) and 417.2 mg of 3- (piperazin-1-yl) -benzonitrile obtained from the previous step in 30 mL of dichloromethane; then 0.74 mL of triethylamine is added.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole
  • 3- (piperazin-1-yl) -benzonitrile obtained from the previous step in 30 mL of dichloromethane; then 0.74 mL of
  • the reaction mixture is stirred at 20 ° C for 16 hours and then diluted with 50 mL of dichloromethane and 50 mL of water. After decantation, the mixture is extracted with 20 ml of dichloromethane. The organic extracts are combined, washed with a saturated solution of ammonium chloride (20 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure.
  • the crude compound obtained is purified by chromatography on silica gel (Bondelut cartridge, Ref 15111.1000, 26 mm diameter, 20 g of silica 15-40 microns), eluting at a flow rate of 12 ml / min with a mixture of cyclohexane and cyclohexane.
  • Step 3 Starting from 130.1 mg of 3- [4- (3-phenyl-1H-pyrrol-2-ylcarbonyl) -piperazin-1-yl] -benzonitrile obtained above, in solution in dimethylformamide (1.5 ml) then 13 mg of sodium hydride and 61.4 mg of methyl bromoacetate are added and allowed to react at 20 ° C for 1.5 hours. The reaction being incomplete, a portion of sodium hydride (14 mg) and methyl bromoacetate (43 ⁇ l) are added.
  • reaction mixture is treated as follows: dilution with water (20 ml) and ethyl acetate (20 ml), decantation, extraction with ethyl acetate ( 2x15 ml). The organic extracts are combined, dried over magnesium sulphate and then evaporated under pressure scaled down.
  • the compound obtained is purified by chromatography on silica gel (AIT cartridge, ref FC-25Si-HP), eluting with a mixture of dichloromethane and methanol, 90/10 vol / vol at a flow rate of 10 ml / min.
  • Step 4 In a 50 ml flask containing 95 mg of methyl ⁇ 2- [4- (3-cyano-phenyl) -piperazin-1-yl-carbonyl] -3-phenyl-pyrrol-1-yl ⁇ -acetate obtained previously, a solution of 0.1 M sodium hydroxide solution (491 ⁇ l) and methanol (3 ml) is added. The reaction mixture is stirred under reflux for 48 hours. The reaction is not complete, we introduce an additional portion of sodium hydroxide (250 .mu.l) while maintaining the reflux overnight.
  • reaction mixture is evaporated to dryness and then purified by reversed-phase high performance chromatography (injection volume 5 ml DMSO, Nucleodur column, C18 100-10, 250x40 mm, ref 762020, serial no. 3051181, lot 2023). using a water / acetonitrile gradient (containing 0.07% of trifluoroacetic acid, from 95/5 to 5/95 -proportions in volumes- in 52 minutes at a flow rate of 75 ml / min). The fractions containing the expected compound are combined and evaporated.
  • Step 2 The procedure is as in Example 5, but starting from 202 mg of 2-methyl-4-phenyl-1H-imidazol-5-yl-carboxylic acid on the one hand and 265 on the other hand.
  • EDCI 1- (3-dimethylaminopropyl) -3-hydrochloride ethylcarbodiimide
  • HOBT 1-hydroxybenzotriazole hydrate
  • Step 2 To a solution of 95 mg of 3- ⁇ 4- [1- (tert-butyl-dimethyl-silanyloxy) -ethyl-2-phenyl-1H-pyrrol-3-yl-carbonyl] -piperazin-1-yl ⁇ -benzamide.
  • Example 5 The procedure is as in Example 5, but starting from 265 mg of 2-mercapto-4-phenyl-1H-imidazol-5-yl-carboxylic acid, obtained according to Chem. Pharm. Bull. 1984, 32 (7), 2536-43, and on the other hand 220 mg of (3-hydroxy-phenyl) -piperazine dihydrochloride, obtained as in step 1 of Example 57, in 25 ml of dichloromethane in the presence of 211 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 148 mg of 1-hydroxybenzotriazole hydrate (HOBT) and 309 ⁇ l of triethylamine, with stirring at room temperature for 20 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Example 5 The procedure is as in Example 5, but starting from 521 mg of 2-mercapto-4-phenyl-1H-imidazol-5-yl-carboxylic acid, obtained as in step 1 of Example 67, and on the other hand 530 mg of (3-hydroxy-phenyl) -piperazine dihydrochloride, obtained as in Step 1 of Example 57, in 50 ml of dichloromethane, in the presence of 422 mg of hydrochloride.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide
  • HOBT 1-hydroxybenzotriazole hydrate
  • Example 5 The procedure is as in Example 5, but starting with 157 mg of 1-methyl-2-phenyl-1H-pyrrol-3-ylcarboxylic acid, which can be prepared according to Med. Chem. Res. (1997), 7 (2), 98-108, and on the other hand 227 mg of (3-hydroxy-phenyl) -piperazine dihydrochloride, obtained as in step 1 of Example 57, in 50 ml. of dichloromethane, in the presence of 165 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 12 mg of 1-hydroxybenzotriazole hydrate (HOBT) and 240 ⁇ l of triethylamine, with stirring at room temperature.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Step 1 430 mg of 3- [4- (2-phenyl-1H-pyrrol-3-ylcarbonyl) piperazin-1-yl] benzonitrile, prepared in Example 74, are dissolved in 20 mL of anhydrous pyridine. After cooling to 0 ° C., 72 mg of 60% sodium hydride in oil, previously washed by decantation in toluene, are added portionwise, the mixture is stirred at 0 ° C. for 30 minutes. 0.28 ml of (2-bromoethoxy) -fetf-butyl-dimethylsilane are then added and the mixture is stirred at ambient temperature for 20 hours.
  • Step 2 To a solution of 550 mg of 3- ⁇ 4- [1- (tert-butyl-dimethyl-silanyloxy) -ethyl-2-phenyl-1H-pyrrol-3-yl-carbonyl] -piperazin-1 yl ⁇ -benzonitrile in
  • Example 5 The procedure is as in Example 5, but on the one hand 256 mg of 2-trifluoromethyl-4-phenyl-1-H-imidazol-4-yl-carboxylic acid, prepared as in step 1 of Example 54, and on the other hand 265 mg of 1- (3-hydroxymethyl-phenyl) -piperazine dihydrochloride, prepared as in Step 1 of Example 57, in 25 ml of dichloromethane, in the presence of 211 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 148 mg of 1-hydroxybenzotriazole hydrate (HOBT) and 309 ⁇ l of triethylamine, with stirring at room temperature for 20 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Example 5 The procedure is as in Example 5, but on the one hand 256 mg of 2-trifluoromethyl-4-phenyl-1-H-imidazol-4-yl-carboxylic acid, prepared as in step 1 of Example 54, and 260 mg of 1- (3-cyanomethyl-phenyl) -piperazine dihydrochloride, prepared according to Tetrahedron Lett. 2000, 56 (24), 4107-10, in the presence of 211 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 149 mg of 1-hydroxybenzotriazole hydrate (HOBT) and 309 ⁇ L of triethylamine, with stirring at room temperature for 20 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Example 5 The procedure is as in Example 5, but starting from 256 mg of 2-phenyl-1H-pyrrol-3-yl-carboxylic acid, prepared as in Step 2 of Example 21, and on the other hand 265 mg of 1- (3-hydroxymethyl-phenyl) -piperazine dihydrochloride, prepared as in step 1 of Example 57, in the presence of 211 mg of 1- (3-dimethylaminopropyl) hydrochloride. 3-ethylcarbodiimide (EDCI), 149 mg of 1-hydroxybenzotriazole hydrate (HOBT) and 309 ⁇ l of triethylamine, with stirring at room temperature for 20 hours.
  • EDCI 3-ethylcarbodiimide
  • HOBT 1-hydroxybenzotriazole hydrate
  • Step 1 500 mg of 3- [4- (4-phenyl-1H-pyrrol-3-ylcarbonyl) piperazin-1-yl] benzonitrile, prepared as in Example 61, are dissolved in 15 ml of dimethylformamide (DMF) anhydrous. After cooling to 0 ° C., 62 mg of 60% sodium hydride in oil, previously washed by decantation in toluene, are added portionwise, the mixture is stirred at 0 ° C. for 30 minutes. 370 mg of (2-bromo-ethoxy) -fer-butyl-dimethyl-silane are then added and the mixture is stirred at room temperature for 20 hours.
  • DMF dimethylformamide
  • the reaction medium is taken up in 50 ml of water and then extracted with 3 times 25 ml of ethyl acetate. After drying over magnesium sulphate and concentration under reduced pressure, the residue is purified by flash chromatography on silica gel (60, 30-75 ⁇ M) eluting with ethyl acetate.
  • silica gel 60, 30-75 ⁇ M
  • Step 2 To a solution of 720 mg of 3- ⁇ 4- [1- (tert-butyl-dimethyl-silanyloxy) -ethyl-4-phenyl-1H-pyrrol-3-yl-carbonyl] -piperazin-1 yl ⁇ -benzonitrile in
  • Step 1 Dissolve 240 mg of [4- (3-hydroxymethyl-phenyl) -piperazin-1-yl] - (2-phenyl-1H-pyrrol-3-yl] -methanone prepared as in Example 86 In 40 ml of anhydrous pyridine, after cooling to 0 ° C., 40 mg of 60% sodium hydride in oil, previously washed by decantation in toluene, are added portionwise, stirred at 0 ° C. for 30 minutes.
  • Step 2 To a solution of 98 mg of [4- (3-hydroxymethyl-phenyl) -piperazin-1-yl] - (1 - (tert-butyl-dimethyl-silanyloxy) ethyl-2-phenyl-1H-pyrrol 5 mL of methanone in 5 mL of tetrahydrofuran are added 1, 5 mL of a 1M solution of tetra-N-butylammonium fluoride in tetrahydrofuran, and the mixture is stirred for 20 hours at 20 ° C.
  • Step 2 The procedure is as in Example 5, but starting from 200 mg of 2- (2-methoxy-ethyl) amino-4-phenyl-thiazol-5-yl-carboxylic acid and on the other hand 160 mg of (3,5-dimethylphenyl) piperazine in 20 ml of dichloromethane, in the presence of 151 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 107 mg of 1-hydroxybenzotriazole hydrate (HOBT), with stirring at room temperature for 72 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Example 90 and on the other hand 160 mg of (3,5-dimethoxy-phenyl) piperazine in 20 ml of dichloromethane, in the presence of 151 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 107 mg of 1-hydroxybenzotriazole hydrate (HOBT), with stirring at room temperature for 20 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Step 1 750 mg of ethyl 2-hydroxy-4-phenyl-thiazol-5-yl-carboxylate, which can be obtained according to Acta Bote Pharmaceutica 1984, 41 (6), 633-40, are dissolved in 8 ml of Ethanol, then 7.5 mL of a 2.5 N aqueous solution of sodium hydroxide is added and refluxed for 15 minutes. After concentrating the ethanol under reduced pressure, 20 ml of water are added and the mixture is acidified to pH 1 by addition of a 1N aqueous solution of hydrochloric acid. The precipitate formed is drained, washed with water and with diisopropyl ether. There is thus obtained 0.6 g of 2-hydroxy-4-phenyl-thiazol-5-yl-carboxylic acid, in the form of a yellow solid, used as such in the next step, the characteristic of which is as follows:
  • Step 2 The procedure is as in Example 5, but starting from 400 mg of 2-hydroxy-4-phenyl-thiazol-5-yl-carboxylic acid on the one hand, and of 402 mg of (3,5-dimethoxy-phenyl) -piperazine in 50 ml of dichloromethane in the presence of 381 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 269 mg of 1-hydroxybenzotriazole hydrate (HOBT), stirring at room temperature for 20 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Example 5 The procedure is as in Example 5, but starting with 200 mg of 2-hydroxy-4-phenyl-thiazol-5-yl-carboxylic acid, obtained as in Step 1 of Example 95. and 251 mg of (3-carboxamido-phenyl) -piperazine dihydrochloride in 25 ml of dichloromethane, in the presence of 190 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 134 mg of 1-hydroxybenzotriazole hydrate (HOBT) and 279 ⁇ l of triethylamine, with stirring at room temperature for 20 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Example 5 The procedure is as in Example 5, but starting from 308 mg of 4-phenyl-thiazol-5-yl-carboxylic acid, which can be obtained according to Acta Bote Pharmaceutica 1984, 41 (6), 633 -40, and on the other hand 417 mg of (3-carboxamido-phenyl) -piperazine dihydrochloride in 37.5 ml of dichloromethane, in the presence of 316 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 223 mg of 1-hydroxybenzotriazole hydrate (HOBT) and 464 ⁇ l of triethylamine, with stirring at room temperature for 20 hours.
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • Example 5 The procedure is as in Example 5, but starting on the one hand with 100 mg of 2- (2-methoxy-ethyl) amino-4-phenyl-thiazol-5-yl-carboxylic acid, obtained in step 1 of Example 90, and 93.5 mg of (3-cyano-phenyl) -piperazine dihydrochloride, which can be prepared according to Tetrahedron Lett.
  • Tubulin is purified from porcine brains according to published methods (Shelanski et al., 1973, Proc Natl Acad Sci.USA, 70, 765-768, Weinberger et al., 1975, Proc Natl Acad Sci. USA, 72, 1858-1862). Briefly, the brains are crushed and centrifuged in extraction buffer. The tubulin contained in the supernatant of the extract undergoes two successive cycles of polymerization at 37 ° C. and depolymerization at 4 ° C., before being separated from the MAPs (Microtubule Associated Proteins) by chromatography on a phosphocellulose P11 column (Whatman). . The tubulin thus isolated is more than 95% pure.
  • MAPs Microtubule Associated Proteins
  • RB / 2 30% glycerol the composition of which is MES-NaOH [2- (N-morpholino) -ethanesulfonic acid] 50 mM, pH 6.8; MgCl 2 0.25 mM; 0.5 mM EGTA; glycerol 30% (v / v), GTP (guanosine-5'-triphosphate) 0.2 mM.
  • tubulin is adjusted to a concentration of 10 ⁇ M (1 mg / ml) in 30% glycerol RB / 2 buffer to which 1 mM GTP and 6 mM MgCl 2 are added .
  • the polymerization is triggered by an increase of the temperature of 6 ° C to 37 ° C in a vessel of 1 cm optical path, placed in a UVIKON 931 spectrophotometer (Kontron) equipped with a thermostatically controlled cell holder.
  • the increase in the turbidity of the solution is monitored at 350 nm.
  • IC 50 is defined as the concentration of product that inhibits the rate of polymerization by 50%.
  • a product whose IC 50 is less than or equal to 25 ⁇ M is considered very active.
  • a product according to the invention may be useful for inhibiting the proliferation of tumor cells in vitro.
  • HCT116 cells The proliferation of HCT116 cells was evaluated by measuring [ 14 C] -thymidine incorporation as follows.
  • HCT116 cells (from ATCC) are cultured in DMEM medium (Gibco) which contains 10% fetal calf serum and antibiotics (penicillin 1%, streptomycin 1%).
  • DMEM medium Gibco
  • antibiotics penicillin 1%, streptomycin 1%
  • the cells are seeded in 96-well cytostar microplates (Amersham), at a rate of 5000 cells per well.
  • [ 14 C] thymidine 0.1 ⁇ Ci / well
  • Variable concentrations of products up to 10 ⁇ M are used; the DMSO (solvent used to solubilize the products) must not exceed 0.5% in the medium.
  • IC 50 is defined as the concentration of product that decreases radioactivity by 50% compared to an untreated control. It is considered that a product whose Cl 50 is less than 10 ⁇ M is cytotoxic Biological results

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WO2007021573A1 (en) * 2005-08-15 2007-02-22 Astrazeneca Ab Substituted piperazines as metabotropic glutamate receptor antagonists
WO2007119833A1 (ja) * 2006-04-14 2007-10-25 Takeda Pharmaceutical Company Limited 含窒素複素環化合物
WO2007141039A1 (de) * 2006-06-09 2007-12-13 Grünenthal GmbH 1,3-disubstituierte 4-methyl-1 h-pyrrol-2-carbonsäureamide und ihre verwendung zur herstellung von arzneimitteln
WO2013111831A1 (ja) * 2012-01-25 2013-08-01 株式会社ヤクルト本社 ピロール化合物

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US20050119251A1 (en) * 2001-12-21 2005-06-02 Jian-Min Fu Nicotinamide derivatives and their use as therapeutic agents
WO2006034441A1 (en) * 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors
WO2006034312A1 (en) * 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Bicyclic heterocyclic derivatives and their use as inhibitors of stearoyl-coa-desaturase (scd)
TW200626138A (en) * 2004-09-20 2006-08-01 Xenon Pharmaceuticals Inc Heterocyclic derivatives and their use as therapeutic agents
EP2316457A1 (en) * 2004-09-20 2011-05-04 Xenon Pharmaceuticals Inc. Pyridine derivatives for inhibiting human stearoyl-coa-desaturase
CA2580857A1 (en) * 2004-09-20 2006-09-28 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors
JP5094398B2 (ja) * 2004-09-20 2012-12-12 ゼノン・ファーマシューティカルズ・インコーポレイテッド 複素環式誘導体およびステアロイル−ＣｏＡデサチュラーゼのメディエータとしてのそれらの使用
WO2006034440A2 (en) 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors
MX2007003318A (es) 2004-09-20 2007-05-18 Xenon Pharmaceuticals Inc Derivados heterociclicos y su uso como agentes terapeuticos.
WO2006034341A2 (en) * 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-coa-desaturase
AU2006343359A1 (en) 2005-06-03 2007-11-15 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-coa desaturase inhibitors
US8148367B2 (en) * 2007-01-12 2012-04-03 Takeda Pharmaceutical Company Limited Renin inhibitors
US9271962B2 (en) * 2008-03-17 2016-03-01 Northeastern University Inhibitors of fatty acid amide hydrolase and monoacylglycerol lipase for modulation of cannabinoid receptors
AU2009330821B2 (en) 2008-12-24 2015-06-11 Bial - Portela & Ca, S.A. Pharmaceutical compounds
KR101297652B1 (ko) * 2010-11-25 2013-08-19 한국과학기술연구원 항암활성을 지닌 카르보아졸계 화합물
EA029899B1 (ru) 2012-06-04 2018-05-31 Идорсиа Фармасьютиклз Лтд Производные бензимидазол-пролина
WO2014057435A1 (en) 2012-10-10 2014-04-17 Actelion Pharmaceuticals Ltd Orexin receptor antagonists which are [ortho bi (hetero )aryl]-[2-(meta bi (hetero )aryl)-pyrrolidin-1-yl]-methanone derivatives
CA2902135A1 (en) 2013-03-12 2014-09-18 Actelion Pharmaceuticals Ltd Azetidine amide derivatives as orexin receptor antagonists
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WO2007021573A1 (en) * 2005-08-15 2007-02-22 Astrazeneca Ab Substituted piperazines as metabotropic glutamate receptor antagonists
WO2007119833A1 (ja) * 2006-04-14 2007-10-25 Takeda Pharmaceutical Company Limited 含窒素複素環化合物
WO2007141039A1 (de) * 2006-06-09 2007-12-13 Grünenthal GmbH 1,3-disubstituierte 4-methyl-1 h-pyrrol-2-carbonsäureamide und ihre verwendung zur herstellung von arzneimitteln
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